荷兰阿姆斯特丹大学Doortje Rademaker团队比较了口服降糖药与胰岛素治疗妊娠期糖尿病对围产期结局的影响。相关论文于2025年1月6日发表在《美国医学会杂志》上。

二甲双胍和格列本脲单一疗法被用作治疗妊娠期糖尿病的胰岛素替代品。与单独使用胰岛素相比，这些口服药物的序贯策略是否会导致非劣效的围产期结局尚不清楚。

为了探讨口服降糖药预防大于胎龄儿的治疗策略是否不劣于胰岛素，2016年6月至2022年11月，研究组在荷兰25个医学中心进行了随机、开放标签的非劣效性试验，随访于2023年5月完成。该研究招募了820名妊娠16至34周、单胎妊娠的妊娠期糖尿病患者，她们在2周的饮食改变后血糖控制不足（定义为空腹血糖>95 mg/dL[>5.3 mmol/L]，餐后1小时血糖>140 mg/dL[>7.8 mmol/L]，或餐后2小时血糖>120 mg/dL[>6.7 mmol/L]，通过毛细管葡萄糖自检测量）。

参与者被随机分配接受二甲双胍（起始剂量为500 mg，每日一次，每3天增加一次，至1000mg，每日两次或最高耐受水平；n=409）或胰岛素（根据当地惯例开具；n=411）治疗。若有需要，二甲双胍中加入格列本脲。若血糖控制不理想，用胰岛素代替格列本脲以达到血糖目标。主要结局是组间大于胎龄儿（出生体重>90百分位，基于胎龄和性别）的百分比差异。次要结局包括产妇低血糖、剖宫产、妊娠高血压综合征、先兆子痫、产妇体重增加、早产、出生损伤、新生儿低血糖、新生儿高胆红素血症和新生儿重症监护室入院。

820名参与者的平均年龄为33.2岁（标准差4.7岁）。在随机分配到口服药物组的参与者中，79%（n=320）在没有胰岛素的情况下维持血糖控制。口服药物组，23.9%的婴儿（n=97）胎龄较大，而胰岛素组为19.9%（n=79）（绝对风险差，4.0%；95%CI，-1.7%至9.8%；P = .09 对于非劣效性），风险差异的置信区间超过8%的绝对非劣效边际。口服降糖药和胰岛素的产妇低血糖发生率分别为20.9%和10.9%（绝对风险差为10.0%；95%CI为3.7%-21.2%）。所有其他次要结局在各组之间没有差异。

研究结果表明，与胰岛素相比，二甲双胍和额外的格列本脲（如果需要）治疗妊娠期糖尿病不符合非劣效性标准。

附：英文原文

Title: Oral Glucose-Lowering Agents vs Insulin for Gestational Diabetes: A Randomized Clinical Trial

Author: Doortje Rademaker, Leon de Wit, Ruben G. Duijnhoven, Daphne N. Voormolen, Ben Willem Mol, Arie Franx, J. Hans DeVries, Rebecca C. Painter, Bas B. van Rijn, SUGAR-DIP Study Group, Sarah E. Siegelaar, Bettina M. C. Akerboom, Rosalie M. Kiewiet-Kemper, Marion A. L. Verwij-Didden, Fahima Assouiki, Simone M. Kuppens, Mirjam M. Oosterwerff, Eva Stekkinger, Mattheus J. M. Diekman, Tatjana E. Vogelvang, Gerdien Belle–van Meerkerk, Sander Galjaard, Koen Verdonk, Annemiek Lub, Tamira K. Klooker, Ineke Krabbendam, Jeroen P. H. van Wijk, Anjoke J. M. Huisjes, Thomas van Bemmel, Remco G. W. Nijman, Annewieke W. van den Beld, Wietske Hermes, Solrun Johannsson-Vidarsdottir, Anneke G. Vlug, Remke C. Dullemond, Henrique J. Jansen, Marieke Sueters, Eelco J. P. de Koning, Judith O. E. H. van Laar, Pleun Wouters–van Poppel, Inge M. Evers, Marina E. Sanson–van Praag, Eline S. van den Akker, Catherine B. Brouwer, Brenda B. Hermsen, Ralph Scholten, Rick I. Meijer, Marsha van Leeuwen, Johanna A. M. Wijbenga, Lia D. E. Wijnberger, Arianne C. van Bon, Flip W. van der Made, Silvia A. Eskes, Mirjam Zandstra, William H. van Houtum, Babette A. M. Braams-Lisman, Catharina R. G. M. Daemen-Gubbels, Janna W. Nijkamp, Harold W. de Valk, Maurice G. A. J. Wouters, Richard G. IJzerman, Irwin Reiss, Joris A. M. van der Post, Judith E. Bosmans

Issue&Volume: 2025-01-06

Abstract:

Importance  Metformin and glyburide monotherapy are used as alternatives to insulin in managing gestational diabetes. Whether a sequential strategy of these oral agents results in noninferior perinatal outcomes compared with insulin alone is unknown.

Objective  To test whether a treatment strategy of oral glucose-lowering agents is noninferior to insulin for prevention of large-for-gestational-age infants.

Design, Setting, and Participants  Randomized, open-label noninferiority trial conducted at 25 Dutch centers from June 2016 to November 2022 with follow-up completed in May 2023. The study enrolled 820 individuals with gestational diabetes and singleton pregnancies between 16 and 34 weeks of gestation who had insufficient glycemic control after 2 weeks of dietary changes (defined as fasting glucose >95 mg/dL [>5.3 mmol/L], 1-hour postprandial glucose >140 mg/dL [>7.8 mmol/L], or 2-hour postprandial glucose >120 mg/dL [>6.7 mmol/L], measured by capillary glucose self-testing).

Interventions  Participants were randomly assigned to receive metformin (initiated at a dose of 500 mg once daily and increased every 3 days to 1000 mg twice daily or highest level tolerated; n=409) or insulin (prescribed according to local practice; n=411). Glyburide was added to metformin, and then insulin substituted for glyburide, if needed, to achieve glucose targets.

Main Outcomes and Measures  The primary outcome was the between-group difference in the percentage of infants born large for gestational age (birth weight >90th percentile based on gestational age and sex). Secondary outcomes included maternal hypoglycemia, cesarean delivery, pregnancy-induced hypertension, preeclampsia, maternal weight gain, preterm delivery, birth injury, neonatal hypoglycemia, neonatal hyperbilirubinemia, and neonatal intensive care unit admission.

Results  Among 820 participants, the mean age was 33.2 (SD, 4.7) years). In participants randomized to oral agents, 79% (n=320) maintained glycemic control without insulin. With oral agents, 23.9% of infants (n=97) were large for gestational age vs 19.9% (n=79) with insulin (absolute risk difference, 4.0%; 95% CI, 1.7% to 9.8%; P=.09 for noninferiority), with the confidence interval of the risk difference exceeding the absolute noninferiority margin of 8%. Maternal hypoglycemia was reported in 20.9% with oral glucose-lowering agents and 10.9% with insulin (absolute risk difference, 10.0%; 95% CI, 3.7%-21.2%). All other secondary outcomes did not differ between groups.

Conclusions and Relevance  Treatment of gestational diabetes with metformin and additional glyburide, if needed, did not meet criteria for noninferiority compared with insulin with respect to the proportion of infants born large for gestational age.

DOI: 10.1001/jama.2024.23410

Source: https://jamanetwork.com/journals/jama/fullarticle/2828808